PS516 Unit 9 Research Evaluation Paper Example

Did Psilocybin Beat Escitalopram?: A PS516 Unit 9 Paper Evaluating the 2021 NEJM Trial of Psilocybin for Depression

[Student Name]

Purdue University Global

PS516: Psychopharmacology

Unit 9 Research Evaluation Paper

[Instructor Name]

[Date]

The writer, the clinic and the client who asked are composite; the trial and the sources cited are real.

Why This Study

Last spring Teresa, a client with long-standing depression who has tried two antidepressants, brought a printout of a news article to our session. The headline said that psilocybin, the active ingredient in "magic mushrooms," worked better than a standard antidepressant. She wanted to know whether she should ask our nurse practitioner about it or travel to Oregon, where supervised psilocybin services are legal. To answer her honestly, I read the trial the article described.

What the Trial Did

Carhart-Harris et al. (2021) randomly assigned 59 adults with moderate to severe major depression to one of two groups for six weeks. One group received two doses of 25 milligrams of psilocybin three weeks apart, plus daily placebo capsules. The other received two very low 1-milligram doses of psilocybin, intended to have no meaningful effect, plus daily escitalopram, a standard SSRI antidepressant. Both groups received psychological support before, during and after the dosing sessions. The primary outcome was the change in a self-rated depression scale, the QIDS-SR-16, from baseline to six weeks.

What It Found

The main comparison came out a statistical tie. Depression scores fell in both groups, by a somewhat larger amount in the psilocybin group, but the trial could not show that psilocybin was better than escitalopram on its main measure. Most secondary outcomes, such as response and remission rates and other depression scales, favored psilocybin, but the authors themselves cautioned that these comparisons were not corrected for multiple testing and should not be taken as firm conclusions.

The headline Teresa brought in reported the secondary outcomes as if they were the main result; the main result was a tie.

Strengths

The trial had real strengths. It was randomized and double-blind in design, and it compared psilocybin with an active, established treatment rather than only with placebo, which is a harder test. Both groups received the same psychological support, so differences could not be attributed to extra therapy time. The authors registered the trial and reported their primary outcome clearly, which is how a careful reader can see that the headline went beyond it.

Limits

The sample was small, 59 people, which makes estimates uncertain and limits the ability to detect differences. Participants were mostly white, well educated and had volunteered for a psychedelic study, so they may have expected psilocybin to work. The trial lasted six weeks, much shorter than the time over which depression treatment is usually judged.

Blinding is the most serious problem for any psychedelic trial. Muthukumaraswamy et al. (2021) argue that people who take a full dose of a psychedelic almost always know it, because the experience is unmistakable, and that most published trials did not measure participants' expectations or check whether blinding held. When participants know their treatment, and many of them expect it to work, their self-reported improvement can reflect expectancy as much as the drug. The low-dose comparison group in Carhart-Harris and colleagues' trial was meant to reduce this problem, but it could not remove it.

The comparison with escitalopram also has a complication. Six weeks is about the time an SSRI takes to begin working fully, and Cipriani et al. (2018) found that antidepressants, including escitalopram, outperform placebo over a typical eight-week trial. A six-week comparison may have caught escitalopram before its full effect.

Who Was Left Out

A trial's exclusion rules tell a reader whom its results cannot speak for. Psychedelic trials, including this one, have generally excluded people with a personal or close family history of psychotic disorders, people with recent serious suicide attempts and people with certain medical conditions, because psilocybin can provoke intense and sometimes frightening experiences and raises heart rate and blood pressure for several hours. Teresa has a sister with bipolar disorder, which would very likely have kept her out of the study. That alone means the trial's results cannot be applied to her without a prescriber's careful judgment.

Reading the Numbers

A careful reader also asks how large the differences were and how certain. The trial reported a difference on the main depression scale that favored psilocybin but whose confidence interval included zero, which is what a nonsignificant result means in practice: the true difference could be small in either direction or moderate in favor of psilocybin. With 59 participants, a trial can easily miss a modest real difference, and it can just as easily produce a promising-looking number by chance. Neither reading justifies a headline.

The outcome measure matters too. The primary scale was self-rated, which is useful because it captures how participants themselves feel, but it is also the kind of measure most sensitive to expectancy when participants know what they received. A clinician-rated scale, given by a rater who does not know the group assignment, is harder to sway, though in a psychedelic trial even raters may guess.

What I Told Teresa

I told Teresa that the study was a serious, well-designed trial, that psilocybin did as well as a standard antidepressant over six weeks and that the trial did not show it was better on its main measure. I explained that people in such trials usually know whether they had the drug, which makes the results harder to interpret, and that more and larger studies are under way. I also explained that psilocybin is not an approved treatment for depression, that the legal Oregon services are not a medical treatment program and that anyone with her history should talk with her prescriber before considering it. She decided to bring the question to our nurse practitioner at her next visit, along with her frustration that two antidepressants had not helped. That frustration was the more urgent issue. Two failed medication trials call for a careful review of diagnosis, dose, duration and whether psychotherapy has been tried, and the nurse practitioner arranged a consultation with our psychiatrist to do just that.

Conclusion

Carhart-Harris and colleagues' trial is an important early study of psilocybin for depression, with strengths in its active comparison and equal psychological support. Its primary result was a tie with escitalopram, and its secondary findings need caution. The blinding and expectancy problems that Muthukumaraswamy and colleagues describe, the small sample and the short duration limit what it can show. For a care manager, the lesson is to read the primary outcome first and to help clients separate a promising study from a proven treatment.

References

Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., & Nutt, D. J. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine, 384(15), 1402-1411. https://doi.org/10.1056/NEJMoa2032994

Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., Leucht, S., Ruhe, H. G., Turner, E. H., Higgins, J. P. T., Egger, M., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Tajika, A., Ioannidis, J. P. A., & Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. The Lancet, 391(10128), 1357-1366. https://doi.org/10.1016/S0140-6736(17)32802-7

Muthukumaraswamy, S. D., Forsyth, A., & Lumley, T. (2021). Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Review of Clinical Pharmacology, 14(9), 1133-1152. https://doi.org/10.1080/17512433.2021.1933434